Ras and autophagy in cancer development and therapy

Abstract

Autophagy, a process of self-degradation and turnover of cellular components, plays a complex role in cancer. Evidence exists to show that autophagy may support tumor growth and cell survival, whereas it can also contribute to tumor suppression and have anti-survival characteristics in different cellular systems. Numerous studies have described the effects of various oncogenes and tumor suppressors on autophagy. The small GTPase Ras is an oncogene involved in the regulation of various cell-signaling pathways, and is mutated in 33% of human cancers. In the present review, we discuss the interplay between Ras and autophagy in relation to oncogenesis. It appears that Ras can upregulate or downregulate autophagy through several signaling pathways. In turn, autophagy can affect the tumorigenicity driven by Ras, resulting in either tumor progression or repression, depending on the cellular context. Furthermore, Ras inhibitors were shown to induce autophagy in several cancer cell lines.

Figure 1. Ras signaling regulates autophagy

Ras-mediated upregulation (green) or downregulation (red) of autophagy is depicted in the scheme. Ras can promote autophagy via the Rac1/MKK7/JNK pathway and subsequent upregulation of Atg5/Atg7 [42, 44]. Ras was also shown to induce autophagy through the Raf-1/MEK1/2/ERK pathway which inhibits the binding of Bcl-2/Mcl-1 to beclin 1 leading to the formation of the class III PI3K complex [38, 41], or in a GAIP-mediated manner [40]. Inhibition of autophagy by Ras is mediated by the activation of the class I PI3K/Akt/mTOR1 pathway and subsequent inhibition of the ULK1/Atg13/FIP200 complex [35, 37]. Autophagy induced by Ras can, in turn, affect tumor progression by modulating cell death, cell proliferation, mitochondrial integrity and sensitivity to matrix detachment and metabolic stress.